POS0326 THE ΤRANSCRIPTOMIC LANDSCAPE OF ACTIVE PSORIATIC ΑRTHRITIS: ACTIVATED INNATE ΙMMUNITY, EXTRACELLULAR MATRIX (ECM) TURNOVER, ABERRANT METABOLISM AND HEMOPOIETIC CELL - SKIN CROSSTALK.
Authors: A. Grivas, M. Grigoriou, G. Sentis, A. Filia, P. Katsimpri, P. Verginis, D. Boumpas
Journal: Annals of the Rheumatic Diseases (2022)

Background Psoriatic arthritis (PsA) is a chronic inflammatory disease whereby activated T lymphocytes and myeloid cells interact with tissue-resident cells in the skin and joints. Gene expression studies, mainly based on the microarray platforms, have provided an initial glimpse into disease pathogenesis highlighting, among others, the role of the TNFα and IL17 cytokine axis. Yet, the transcriptomic landscape of PsA remains largely unexplored, and the specific contribution of skin fibroblasts to disease pathogenesis remains elusive. Objectives To comprehensively characterize the gene expression profile in PsA, specifically in the blood and skin fibroblasts through next-generation RNA sequencing. Methods Peripheral blood (PB) was collected from PsA patients (n=30) after informed consent. Healthy individuals (HC) and patients with rheumatoid arthritis (RA) were used as healthy and disease controls (n=10/group) respectively. Psoriatic skin biopsies were obtained from a subset of three PsA patients and three HC. All PsA patients fulfilled the CASPAR criteria and displayed peripheral polyarthritis of moderate- to high- disease activity. Patient’s clinical and laboratory data were recorded at the time of sampling. Disease activity in PsA and RA was assessed using the Disease Activity Index for Psoriatic arthritis (DAPSA) and the Disease Activity Score-28 (DAS28), respectively. RNA from PB and skin fibroblasts was extracted, RNA libraries were prepared and sequenced. EdgeR package was used to call differentially expressed genes (DEGs). Statistical significance was set at p value&lt;0.05 and fold-change |FC| &gt;1.5. Functional enrichment analysis and weighted gene co-expression network analysis (WGCNA) was implemented. Inference and analysis of blood immune cells-skin fibroblasts communication were performed with CellChat. Results 8 males and 22 female patients with PsA were included with median age 49 years old and median disease duration 4 years. The median DAPSA score was 44.3 and the median DAS28 score was 5.5 for RA patients, suggesting high disease activity in both groups. We found 466 DEGs in PsA versus HC blood (303 up- and 163 down-regulated). DEGs were significantly enriched in biological pathways related to immunity (i.e. inflammatory response, TNFa signaling via NFkB, IFNa &amp; IFNγ response, complement, IL2 signaling ), metabolism (i.e. oxidative phosphorylation, adipogenesis, fatty acid metabolism ) and other signaling cascades of pathophysiologic relevance (i.e. WNTb catenin signaling, TGFβ signaling, MTORC1 signaling ). WGCNA in blood revealed four gene modules containing highly correlated genes. These modules were enriched in myeloid leukocyte mediated immunity , neutrophil-mediated immunity , ECM and collagen metabolism, TGFβ and PDGF signaling . Next, we characterized the “PsA specific activity signature”, taking the intersection of DEGs in ‘PsA vs. HC’ and ‘PsA vs. RA’, which resulted in 67 DEGs enriched in response to TGF and PDGF , ECM organization and degradation. CellChat analysis identified a higher number of interactions between blood immune cells and skin fibroblasts and increased strength of interactions in PsA compared to healthy state. Aberrant interactions between blood and skin fibroblasts in PsA included, among others, ligand-receptor pairs of the WNT, Notch, and GDF11 signaling pathways. Conclusion Our findings confirm the presence of an IFNα signature and complement activation in PsA. The increased cardiometabolic burden and enhanced bone remodeling are reflected by the presence of pathways related to aberrant metabolism and ECM metabolism, respectively. The myeloid cell signature in active disease supports the emerging role of monocytes/macrophages in driving inflammation in PsA, while the aberrant blood-skin fibroblast interactions suggest a novel role for these resident cells in disease pathophysiology. References [1]Bravo A. et al. Nat Rev Rheumatol. 2019 Nov;15(11):645-656. doi: 10.1038/s41584-019-0285-8. Disclosure of Interests None declared